Enhancing tumor response to targeted chemotherapy through up-regulation of folate receptor α expression induced by dexamethasone and valproic acid - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Journal of Controlled Release Année : 2018

Enhancing tumor response to targeted chemotherapy through up-regulation of folate receptor α expression induced by dexamethasone and valproic acid

F. Guilhot
  • Fonction : Auteur

Résumé

Several folate-drug conjugates are currently undergoing clinical trials for application in oncology. However, the efficacy of folate-targeted therapy strongly depends on the folate receptor (FR) abundance at the surface of cancer cells. Recently, it has been postulated that up-regulation of FRα by means of chemo-sensitizing agents could enhance the anticancer activity of FR-drug conjugates. In this study, we demonstrate in vitro that a combination of dexamethasone (Dexa) and valproic acid (VPA) increases FRα expression selectively at the surface of FR-overexpressing cancer cells. The same stimulation was observed in vivo in KB-tumor xenografts when mice are treated with this combined treatment. This effect is reversible since treatment interruption induces the return of FR expression at basal level. When incubated with Dexa and VPA, the β-galactosidaseresponsive folate-monomethyl auristatin E (MMAE) conjugate, called MGAF, exhibits higher cytotoxic activity on several FR-positive human cancer cell lines, compared to its administration as a single agent. This improved toxicity results from the enhanced concentration of MMAE released within cancer cells after internalization and subsequent enzymatic activation of MGAF. Higher deposition of MMAE is also observed in vivo after up-regulation of FR expression level in tumor xenografts, induced by the prior administration of the Dexa/VPA combination. In this model, MGAF/Dexa/VPA combined therapy results in an 81% inhibition of tumor growth compared to the control group, while MGAF used in monotherapy is inefficient. Since Dexa and VPA are currently used in humans, this finding could be of great interest for further development of folate-drug conjugates, in particular for those that are presently under clinical investigation.
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Dates et versions

hal-02122599 , version 1 (26-02-2021)

Identifiants

Citer

E. Peraudeau, L. Cronier, A. Monvoisin, P. Poinot, C. Mergault, et al.. Enhancing tumor response to targeted chemotherapy through up-regulation of folate receptor α expression induced by dexamethasone and valproic acid. Journal of Controlled Release, 2018, 269, pp.36-44. ⟨10.1016/j.jconrel.2017.11.011⟩. ⟨hal-02122599⟩
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